RNF220, also known as Ring finger protein 220, is an evolutionarily conserved RING-type ubiquitin E3 ligase. It plays crucial roles in multiple cellular processes. It is involved in pathways such as Wnt, interferon-STAT1, and sonic hedgehog (Shh) signaling, and is of great biological importance in vertebrate embryo development, including neural development, and is also associated with cancer progression and immune response [5]. Genetic models, like KO/CKO mouse models, have been instrumental in studying its functions.

In KO mouse models, RNF220 knockout specifically increases AMPA receptor protein levels, enhancing basal synaptic activity but impairing synaptic plasticity, and also altering learning and memory, indicating its role in excitatory synaptic transmission and brain function [1]. RNF220 depletion in oligodendrocyte lineage cells impedes oligodendrocyte progenitor cell proliferation, differentiation, and (re)myelination, leading to learning and memory defects, as it targets Olig1/2 for K63-linked polyubiquitination and stabilization during oligodendroglial development [2]. Rnf220 gene deficiency results in downregulation of IFN signaling and decreased expression of ISGs in response to type 1 and 2 IFNs stimulation and infections, showing its role in innate immune responses [3]. In Rnf220-deficient mice, the development of central noradrenergic neurons is affected as the Rnf220/Zc4h2 complex monoubiquitylates Phox2a/Phox2b required for their full transcriptional activity [4]. In Rnf220 Nestin CKO mice, alterations in progenitor domains in the ventral ventricular zone of the hindbrain are observed, along with changes in post-mitotic cells, suggesting its role in hindbrain dorsoventral patterning [6]. RNF220+/-; Ptch1+/- mice show lower spontaneous medulloblastoma occurrence compared with Ptch1+/- mice, indicating its role in regulating medulloblastoma progression [7].

In conclusion, RNF220 is essential for multiple biological processes including neural development, immune response, and synaptic function. The KO/CKO mouse models have significantly contributed to understanding its roles in diseases such as leukodystrophy, medulloblastoma, and those related to neural development and immune-related disorders. It also plays roles in cancer-related processes like in gastric cancer and leukaemia, highlighting its broad importance in both normal biological functions and disease conditions.

References:

1. Ma, Pengcheng, Wan, Li Pear, Li, Yuwei, Mao, Bingyu, Sheng, Nengyin. 2022. RNF220 is an E3 ubiquitin ligase for AMPA receptors to regulate synaptic transmission. In Science advances, 8, eabq4736. doi:10.1126/sciadv.abq4736. https://pubmed.ncbi.nlm.nih.gov/36179027/

2. Li, Yuwei, Wan, Li Pear, Song, Ning-Ning, Sheng, Nengyin, Ma, Pengcheng. 2024. RNF220-mediated K63-linked polyubiquitination stabilizes Olig proteins during oligodendroglial development and myelination. In Science advances, 10, eadk3931. doi:10.1126/sciadv.adk3931. https://pubmed.ncbi.nlm.nih.gov/38324685/

3. Guo, Xiaomin, Ma, Pengcheng, Li, Yuwei, Mao, Bingyu, Qi, Xiaopeng. 2020. RNF220 mediates K63-linked polyubiquitination of STAT1 and promotes host defense. In Cell death and differentiation, 28, 640-656. doi:10.1038/s41418-020-00609-7. https://pubmed.ncbi.nlm.nih.gov/32814877/

4. Song, Ning-Ning, Ma, Pengcheng, Zhang, Qiong, Mao, Bingyu, Ding, Yu-Qiang. 2020. Rnf220/Zc4h2-mediated monoubiquitylation of Phox2 is required for noradrenergic neuron development. In Development (Cambridge, England), 147, . doi:10.1242/dev.185199. https://pubmed.ncbi.nlm.nih.gov/32094113/

5. Ma, Pengcheng, Mao, Bingyu. 2021. The many faces of the E3 ubiquitin ligase, RNF220, in neural development and beyond. In Development, growth & differentiation, 64, 98-105. doi:10.1111/dgd.12756. https://pubmed.ncbi.nlm.nih.gov/34716995/

6. Wang, Yu-Bing, Song, Ning-Ning, Zhang, Lei, Mao, Bingyu, Ding, Yu-Qiang. 2022. Rnf220 is Implicated in the Dorsoventral Patterning of the Hindbrain Neural Tube in Mice. In Frontiers in cell and developmental biology, 10, 831365. doi:10.3389/fcell.2022.831365. https://pubmed.ncbi.nlm.nih.gov/35399523/

7. Ma, Pengcheng, An, Tao, Zhu, Liang, Li, Yan, Mao, Bingyu. 2020. RNF220 is required for cerebellum development and regulates medulloblastoma progression through epigenetic modulation of Shh signaling. In Development (Cambridge, England), 147, . doi:10.1242/dev.188078. https://pubmed.ncbi.nlm.nih.gov/32376680/